EP0122219B1 - Substituted carboxylic-acid resins, process for their manafacture, use thereof and pharmaceutical compositions containing these resins - Google Patents

Substituted carboxylic-acid resins, process for their manafacture, use thereof and pharmaceutical compositions containing these resins Download PDF

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Publication number
EP0122219B1
EP0122219B1 EP84810008A EP84810008A EP0122219B1 EP 0122219 B1 EP0122219 B1 EP 0122219B1 EP 84810008 A EP84810008 A EP 84810008A EP 84810008 A EP84810008 A EP 84810008A EP 0122219 B1 EP0122219 B1 EP 0122219B1
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Prior art keywords
resinate
formula
resin
acid
resins
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German (de)
French (fr)
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EP0122219A3 (en
EP0122219A2 (en
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Satish Chandra Dr. Khanna
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Novartis AG
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Ciba Geigy AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/44—Preparation of metal salts or ammonium salts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the resinate of the formula wherein Am® means a strongly basic styrene-divinylbenzene copolymer which is present in cationic form and which contains the sum of m + n quaternary ammonium groups, and the main structural element is the grouping of the formula X 9 is one of the anion of the formula means different anion of an acid, and m and n stands for the total ionic capacity of the copolymer and its molecular weight is about 10 7 to about 10 9 , process for its preparation, its use as an active pharmaceutical ingredient, and pharmaceutical preparations which contain this resinate.
  • Am® means a strongly basic styrene-divinylbenzene copolymer which is present in cationic form and which contains the sum of m + n quaternary ammonium groups
  • the main structural element is the grouping of the formula X 9 is one of the anion of the formula means different anion of an acid
  • m and n stands for the total
  • the sodium salt of diclofenac is used, for example, as a non-steroidal anti-inflammatory in the treatment of inflammatory processes.
  • the corresponding preparations are predominantly administered orally, and also rectally, topically or parenterally.
  • the active substance released from the resinate is mainly absorbed in the alkaline environment of the intestinal tract, where it is not released from the resinate as an acid that is difficult to dissolve in water, but in the form of easily soluble salts.
  • there is also a so-called quick-slow release effect which is quite desirable for this active substance, in comparison to the previously known dosage forms, ie. H. there is first a strong release of the active ingredient and then a slow and only gradually decreasing.
  • the active ingredient release from the resinate according to the invention is surprisingly practically independent of the ionic strength in the gastrointestinal tract, i. H. of its content, which may vary depending on the time of day and eating habits. The advantageous drug delivery characteristic can be seen from the figure.
  • the delivery rate can also be influenced by the choice of the grain size of the resin; the larger the particles, the lower the rate of release of the active ingredient.
  • the particle size is preferably between 20 and 200 ⁇ m, preferably 40 to 100 ⁇ m and the crosslinking between 2 and 8%, preferably 2 to 4%. USP quality is preferably used as the cholestyramine resin.
  • the resinate of the formula is therefore particularly suitable as an anti-inflammatory and as an analgesic for oral or rectal application.
  • the invention also relates to processes for the preparation of the new resinate of the formula I, which can be carried out by methods known per se.
  • a preferred process variant is characterized, for example, in that o- (2,6-dichloroanilino) phenylacetic acid of the formula or a salt thereof with preferably the at least equimolar amount of resin of the formula [Am ⁇ ] [OH ⁇ ] m + n or a salt thereof with an acid, preferably a mineral acid.
  • Anion exchange resins which can be used according to the process are, in particular, cholestyramine, as described, for. B. are available under the brand name Duolite ® A 101D, A 101 D / U, A 102D, A 113, A 116, 143 A 161, A 162 and ES 132 from Diamond Shamrock or Amberlite ® XE 268 P from Rohm and Haas and have a degree of polymerization of approximately 10 8 .
  • Salts of the acid of formula 11 which can be used according to the process are, in particular, salts with bases which can be removed from the reaction mixture, for example inorganic salts, such as, for. B. Alkali salts.
  • the invention further relates to pharmaceutical preparations containing the resinate of the formula I or a process for the production of pharmaceutical preparations.
  • the process is characterized in that the resinate of the formula I is mixed with customary auxiliaries and / or additives and processed to a galenic form.
  • the invention relates in particular to the pharmaceutical preparations and processes for their production described in the examples.
  • compositions according to the invention which contain the resinate of the formula I are those for enteral, such as oral or rectal, administration.
  • the new pharmaceutical preparations are preferably pharmaceutical preparations for enteral administration, e.g. B. those in unit dose forms such as oral and rectal preparations, e.g. B. dragees, tablets, capsules, syrups, drops, suppositories or rectal capsules.
  • compositions are made in a manner known per se, e.g. B. produced by means of conventional mixing, granulating, coating, solution or lyophilization processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active ingredient complex with solid carriers, one obtained Mixture optionally granulated, and the mixture or granulate, if desired or necessary, after the addition of suitable auxiliaries, processed into tablets or coated tablets.
  • Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B. of corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as the starches mentioned above, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.
  • fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphat
  • Aids are primarily flow regulators and lubricants, e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and / or polyethylene glycol.
  • Dragee cores are provided with suitable coatings, u. a. concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide.
  • the tablets or dragee coatings can contain dyes or pigments, e.g. B. for identification or for labeling different doses of active ingredient.
  • compositions are plug-in capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the capsules can the active ingredient complex in the form of granules, for. B. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active substance complex is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
  • Oral connection forms are also drinking suspensions in the form of syrups.
  • the resinate according to the invention decomposes to a small extent during processing and storage, even in the form of a pharmaceutical preparation, and unpleasant-smelling aliphatic amines still occur in large dilution, it is advantageously mixed with odor-binding substances.
  • Activated carbon or cation exchangers based on styrene-divinyl with sulfonic acid or carboxyl groups are particularly useful (see GDR patent specification 147 819).
  • suppositories consist of a combination of the active ingredient with a suppository base.
  • suppository base z.
  • gelatin rectal capsules can also be used, which contain a combination of the active ingredient complex with a base material; come as base materials z.
  • the present invention also relates to the use of the resinate of the formula I, preferably for the treatment of inflammation, primarily inflammatory chronic diseases of the rheumatic type, in particular chronic arthritis.
  • Tablets containing an active ingredient corresponding to 150 mg of diclofenac-Na can be produced as follows:
  • Tablets containing an active ingredient corresponding to 150 mg of diclofenac-Na can be produced as follows:
  • Example 1a 3,000 g of resinate according to Example 1a are thoroughly mixed with 10 g of activated carbon and passed through a sieve with a mesh size of 0.6 mm. The mixture is then filled into 10,000 capsules (size 1). Each capsule contains 150 mg of active ingredient.
  • Duolite® A 161 (average particle size: 80 ⁇ m) are suspended in one liter of 1.5 N sodium hydroxide, and the suspension is heated to 50 ° on a water bath. After 4 to 5 hours the suspension is filtered and the filtrate washed with deionized water. The resin thus obtained is suspended in one liter of 2N hydrochloric acid and stirred at 50 ° for 4 to 5 hours. The resin is filtered off and the filtrate is washed with deionized water. The above steps are repeated twice.
  • the resin obtained is suspended in isopropyl alcohol and stirred for 4 to 5 hours.
  • the resin filtered off is dried at 50 ° in vacuo.
  • Tablets, capsules, suspensions and suppositories can be produced from this resinate as described in Examples 2 to 6.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Polymers & Plastics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

Die Erfindung betrifft das Resinat der Formel

Figure imgb0001
worin Am® ein in kationischer Form vorliegendes, stark basisches Styrol-Divinylbenzol-Copolymeres bedeutet, das die Summe von m + n quaternären Ammoniumgruppen enthält, und das als Hauptstrukturelement die Gruppierung der Formel
Figure imgb0002
aufweist, X9 ein vom Anion der Formel
Figure imgb0003
verschiedenes Anion einer Säure bedeutet, und m und n für die ganze lonenkapazität des Copolymeren steht und dessen Molekulargewicht etwa 107 bis etwa 109 beträgt, Verfahren zu seiner Herstellung, seiner Verwendung als Arzneimittelwirkstoff, sowie pharmazeutische Präparate, die dieses Resinat enthalten.The invention relates to the resinate of the formula
Figure imgb0001
 wherein Am® means a strongly basic styrene-divinylbenzene copolymer which is present in cationic form and which contains the sum of m + n quaternary ammonium groups, and the main structural element is the grouping of the formula
Figure imgb0002
 X 9 is one of the anion of the formula
Figure imgb0003
 means different anion of an acid, and m and n stands for the total ionic capacity of the copolymer and its molecular weight is about 10 7 to about 10 9 , process for its preparation, its use as an active pharmaceutical ingredient, and pharmaceutical preparations which contain this resinate.

Die dem Resinat der Formel 1 zugrundeliegende o-(2,6-Dichloranilino)-phenylessigsäure (Diclofenac) sowie besondere dessen Natriumsalz sind aus der Deutschen Offenlegungsschrift Ns. 1 815 802 bekannt, ebenso deren anti-inflammatorische und analgetische Wirkung. In dem Lehrbuch "Arzneiformenlehre", Dr. P. H. List, 1976, S. 461 und in Remington's Pharmaceutical Science 1975, S. 1626 wird das Prinzip der Resinatbildung beschrieben.The o- (2,6-dichloroanilino) -phenylacetic acid (diclofenac) on which the resinate of formula 1 is based, and in particular its sodium salt, are known from German Offenlegungsschrift No. 1 815 802, as is their anti-inflammatory and analgesic effect. In the textbook "Pharmaceutical Forms", Dr. P.H. List, 1976, p. 461 and Remington's Pharmaceutical Science 1975, p. 1626 describe the principle of resinate formation.

Das Natriumsalz von Diclofenac wird beispielsweise als nicht-steroidales Antiinflammatorikum bei der Behandlung entzündlicher Prozesse eingesetzt. Dabei werden die entsprechenden Präparate überwiegend oral, ferner rektal, topisch oder parenteral, verabreicht.The sodium salt of diclofenac is used, for example, as a non-steroidal anti-inflammatory in the treatment of inflammatory processes. The corresponding preparations are predominantly administered orally, and also rectally, topically or parenterally.

Diese Präparate vermögen jedoch aus verschiedenen Gründen derzeit nicht voll zu befriedigen: So sind bei oraler Applikationsweise Nebenwirkungen möglich, vor allem im oberen Teil des gastrointestinalen Bereichs. Auch hat das Natriumsalz eine lokalanästhesierende Wirkung auf die Mundschleimhäute und Zunge und ist von bitterem Geschmack. Ebenfalls ist die Wirkungsdauer dieser Präparate begrenzt. Im weiteren ist der im Magen freigesetzte Grundkörper des Wirkstoffes, nämlich die Carbonsäure nur wenig wasserlöslich, was je nach Mageninhalt zu einer mehr oder weniger langsamen und unregelmässigen Resorption führt.However, these preparations are currently unsatisfactory for various reasons: side effects are possible with oral administration, especially in the upper part of the gastrointestinal area. The sodium salt also has a local anesthetic effect on the oral mucous membranes and tongue and has a bitter taste. The duration of action of these preparations is also limited. Furthermore, the main body of the active ingredient released in the stomach, namely the carboxylic acid, is only slightly water-soluble, depending on the Gastric contents lead to a more or less slow and irregular absorption.

Diese und weitere bekannte Nachteile des in der Praxis bisher verwendeten Natrium-o-(2,6-dichloranilino)-phenylacetates können durch die Bereitstellung des neuen Resinats der Formel I vermieden oder zumindest erheblich gemildert werden. So ist das erfindungsgemässe Resinat oral wesentlich leichter verabreichbar, da es praktisch geschmacklos ist im Vergleich zum Natriumsalz. Die Geschmacksneutralisierung im Munde ist am besten, wenn das stöchiometrische Verhältnis von Wirkstoff zu Ionenaustauscherharz etwa 1 zu 2 beträgt. Der bevorzugte Verlauf der Wirkstofffreisetzung wird aber am besten mit einem Verhältnis von 1 : 1 erzielt. Obgleich das neue Resinat der Formel I sämtliche erwünschten pharmakologischen Eigenschaften des bekannten Natriumsalzes in zumindest gleicher Wirkungsstärke aufweist, eignet es sich auf Grund seiner spezifischen Vorteile für die orale und rektale Applikation wesentlich besser. So wird der aus dem Resinat freigesetzte Wirkstoff vorwiegend im alkalischen Millieu des Darmtraktes resorbiert, wo er nicht als schwerwasserlösliche Säure, sondern in Form von leicht löslichen Salzen aus dem Resinat freigesetzt wird. Überraschenderweise ergibt sich auch ein für diesen Wirkstoff durchaus erwünschter sogenannter quick-slow release-Effekt im Vergleich zu den bisher bekannten Darreichungsformen, d. h. es erfolgt zuerst eine starke Abgabe des Wirkstoffes und dann eine langsame und nur allmählich abfallende. Überdies ist die Wirkstofffreigabe aus dem erfindungsgemässen Resinat überraschenderweise praktisch unabhängig von der Ionenstärke im Gastrointestinaltrakt, d. h. von seinem Inhalt, der je nach Tageszeit und Ernährungsgewohnheiten verschieden sein kann. Die vorteilhafte Wirkstoffabgabecharakteristik ist aus der Figur ersichtlich.These and other known disadvantages of the sodium o- (2,6-dichloroanilino) phenylacetate previously used in practice can be avoided or at least considerably alleviated by the provision of the new resinate of the formula I. The resinate according to the invention is thus much easier to administer orally, since it is practically tasteless in comparison to the sodium salt. The taste neutralization in the mouth is best when the stoichiometric ratio of active ingredient to ion exchange resin is about 1 to 2. The preferred course of drug release is best achieved with a ratio of 1: 1. Although the new resinate of formula I has all the desired pharmacological properties of the known sodium salt with at least the same potency, it is much more suitable due to its specific advantages for oral and rectal administration. The active substance released from the resinate is mainly absorbed in the alkaline environment of the intestinal tract, where it is not released from the resinate as an acid that is difficult to dissolve in water, but in the form of easily soluble salts. Surprisingly, there is also a so-called quick-slow release effect, which is quite desirable for this active substance, in comparison to the previously known dosage forms, ie. H. there is first a strong release of the active ingredient and then a slow and only gradually decreasing. In addition, the active ingredient release from the resinate according to the invention is surprisingly practically independent of the ionic strength in the gastrointestinal tract, i. H. of its content, which may vary depending on the time of day and eating habits. The advantageous drug delivery characteristic can be seen from the figure.

Die Abgabegeschwindigkeit kann zudem durch die Wahl der Korngrösse des Harzes beeinflusst werden; je grösser die Teilchen, umso geringer ist die Abgabegeschwindigkeit des Wirkstoffes. Die Teilchengrösse liegt vorzugsweise zwischen 20 und 200 µm vorzugsweise 40 bis 100 µm und die Vernetzung zwischen 2 und 8 %, vorzugsweise 2 bis 4 %. Als Cholestyramin-Harz wird vorzugsweise USP-Qualität verwendet.The delivery rate can also be influenced by the choice of the grain size of the resin; the larger the particles, the lower the rate of release of the active ingredient. The particle size is preferably between 20 and 200 μm, preferably 40 to 100 μm and the crosslinking between 2 and 8%, preferably 2 to 4%. USP quality is preferably used as the cholestyramine resin.

Das Resinat der Formel ist dementsprechend vorzüglich als Antiinflammatorikum sowie als Analgetikum zur oralen oder rektalen Applikation verwendbar.The resinate of the formula is therefore particularly suitable as an anti-inflammatory and as an analgesic for oral or rectal application.

Gegenstand der Erfindung sind ebenso Verfahren zur Herstellung des neuen Resinates der Formel I, weicher nach an sich bekannten Methoden erfolgen kann.The invention also relates to processes for the preparation of the new resinate of the formula I, which can be carried out by methods known per se.

Eine bevorzugte Verfahrensvariante ist beispielsweise dadurch gekennzeichnet, dass man o-(2,6-Dichloranilino)-phenylessigsäure der Formel

Figure imgb0004
oder ein Salz davon mit vorzugsweise der mindestens äquimolaren Menge Harz der Formel [Am⊕] [OH⊖]m+n oder einem Salz desselben mit einer Säure, vorzugsweise einer Mineralsäure, umsetzt.A preferred process variant is characterized, for example, in that o- (2,6-dichloroanilino) phenylacetic acid of the formula
Figure imgb0004
 or a salt thereof with preferably the at least equimolar amount of resin of the formula [Am ⊕ ] [OH ⊖ ] m + n or a salt thereof with an acid, preferably a mineral acid.

Verfahrensgemäss verwendbare Anionenaustauscherharze sind insbesondere Cholestyramin, wie es z. B. unter der Markenbezeichnung Duolite® A 101D, A 101 D/U, A 102D, A 113, A 116, 143 A 161, A 162 und ES 132 von Diamond Shamrock oder Amberlite® XE 268 P von Rohm und Haas erhältlich sind und einen Polymerisationsgrad von ungefähr 108 aufweisen.Anion exchange resins which can be used according to the process are, in particular, cholestyramine, as described, for. B. are available under the brand name Duolite ® A 101D, A 101 D / U, A 102D, A 113, A 116, 143 A 161, A 162 and ES 132 from Diamond Shamrock or Amberlite ® XE 268 P from Rohm and Haas and have a degree of polymerization of approximately 10 8 .

Verfahrensgemäss verwendbare Salze der Säure der Formel 11 sind insbesondere Salze mit Basen, die aus dem Reaktionsgemisch entfernt werden können, beispielsweise anorganische Salze, wie z. B. Alkalisalze.Salts of the acid of formula 11 which can be used according to the process are, in particular, salts with bases which can be removed from the reaction mixture, for example inorganic salts, such as, for. B. Alkali salts.

Die Erfindung betrifft weiterhin pharmazeutische Präparate, enthaltend das Resinat der Formel I bzw. ein Verfahren zur Herstellung pharmazeutischer Präparate. Das Verfahren ist dadurch gekennzeichnet, dass man das Resinat der Formel I mit üblichen Hilfs- und/oder Zusatzstoffen vermischt und zu einer galenischen Form verarbeitet.The invention further relates to pharmaceutical preparations containing the resinate of the formula I or a process for the production of pharmaceutical preparations. The process is characterized in that the resinate of the formula I is mixed with customary auxiliaries and / or additives and processed to a galenic form.

Die Erfindung betrifft dabei namentlich die in den Beispielen beschriebenen pharmazeutischen Präparate und Verfahren zu deren Herstellung.The invention relates in particular to the pharmaceutical preparations and processes for their production described in the examples.

Bei den erfindungsgemässen pharmazeutischen Präparaten, welche das Resinat der Formel I enthalten, handelt es sich um solche zur enteralen, wie oralen oder rektalen, Verabreichung.The pharmaceutical preparations according to the invention which contain the resinate of the formula I are those for enteral, such as oral or rectal, administration.

Die neuen pharmazeutischen Präparate sind vorzugsweise pharmazeutische Präparate zur enteralen Verabreichung, z. B. solche in Doseneinheitsformen wie orale und rektale Präparate, z. B. Dragees, Tabletten, Kapseln, Sirupe, Tropfen, Suppositorien oder Rektalkapseln.The new pharmaceutical preparations are preferably pharmaceutical preparations for enteral administration, e.g. B. those in unit dose forms such as oral and rectal preparations, e.g. B. dragees, tablets, capsules, syrups, drops, suppositories or rectal capsules.

Die Präparate werden in an sich bekannter Weise, z. B. mittels konventioneller Misch-, Granulier-, Dragier-, Lösungs- oder Lyophilisierungsverfahren hergestellt. So kann man pharmazeutische Präparate zur oralen Anwendung erhalten, indem man den Wirkstoffkomplex mit festen Trägerstoffen kombiniert, ein erhaltenes Gemisch gegebenenfalls granuliert, und das Gemisch bzw. Granulat, wenn erwünscht oder notwendig, nach Zugabe von geeigneten Hilfsstoffen, zu Tabletten oder Dragees verarbeitet.The preparations are made in a manner known per se, e.g. B. produced by means of conventional mixing, granulating, coating, solution or lyophilization processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient complex with solid carriers, one obtained Mixture optionally granulated, and the mixture or granulate, if desired or necessary, after the addition of suitable auxiliaries, processed into tablets or coated tablets.

Geeignete Trägerstoffe sind insbesondere Füllstoffe, wie Zucker, z. B. Lactose, Saccharose, Mannit oder Sorbit, Cellulosepräparate und/oder Calciumphosphate, z. B. Tricalciumphosphat oder Calciumhydrogenphosphat, ferner Bindemittel, wie Stärkekleister unter Verwendung z. B. von Mais-, Weizen-, Reis oder Kartoffelstärke, Gelatine, Traganth, Methylcellulose und/oder Polyvinylpyrrolidon, und/oder, wenn erwünscht, Sprengmittel, wie die obengenannten Stärken, ferner Carboxymethylstärke, quervernetztes Polyvinylpyrrolidon, Agar, Alginsäure oder ein Salz davon, wie Natriumalginat. Hilfsmittel sind in erster Linie Fliessregulier- und Schmiermittel, z. B. Kieselsäure, Talk, Stearinsäure oder Salze davon, wie Magnesium- oder Calciumstearat und/oder Polyäthylenglykol. Dragee-Kerne werden mit geeigneten Überzügen versehen, wobei man u. a. konzentrierte Zuckerlösungen, welche gegebenenfalls arabischen Gummi, Talk, Polyvinylpyrrolidon, Polyäthylenglycol und/oder Titandioxid enthalten. Den Tabletten oder Dragee-Überzügen können Farbstoffe oder Pigmente, z. B. zur Identifizierung oder zur Kennzeichnung verschiedener Wirkstoffdosen, beigefügt werden.Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B. of corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as the starches mentioned above, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Aids are primarily flow regulators and lubricants, e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and / or polyethylene glycol. Dragee cores are provided with suitable coatings, u. a. concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide. The tablets or dragee coatings can contain dyes or pigments, e.g. B. for identification or for labeling different doses of active ingredient.

Weitere oral anwendbare pharmazeutische Präparate sind Steckkapseln aus Gelatine, sowie weiche, geschlossene Kapseln aus Gelatine und einem Weichmacher, wie Glycerin oder Sorbitol. Die Steckkapseln können den Wirkstoffkomplex in Form eines Granulates, z. B. im Gemisch mit Füllstoffen, wie Lactose, Bindemitteln, wie Stärken, und/oder Gleitmitteln, wie Talk oder Magnesiumstearat, und gegebenenfalls von Stabilisatoren, enthalten. In weichen Kapseln ist der Wirkstoff-Komplex vorzugsweise in geeigneten Flüssigkeiten, wie Fetten Ölen, Paraffinöl oder flüssigen Polyäthylenglycolen, gelöst oder suspendiert, wobei ebenfalls Stabilisatoren zugefügt sein können.Other orally applicable pharmaceutical preparations are plug-in capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can the active ingredient complex in the form of granules, for. B. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance complex is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.

Orale Verbindungsformen sind auch Trinksuspensionen in Form von Sirupen.Oral connection forms are also drinking suspensions in the form of syrups.

Da das erfindungsgemässe Resinat sich bei der Verarbeitung und der Lagerung, selbst in Form eines pharmazeutischen Präparates, in geringem Masse zersetzt, wobei noch in grosser Verdünnung unangenehm riechende aliphatische Amine auftreten, werden ihm vorteilhafterweise geruchsbindende Substanzen beigemischt. Dabei bewähren sich besonders Aktivkohle oder Kationenaustauscher auf Styrol-Divinylbasis mit Sulfonsäure- oder Carboxylgruppen (siehe DDR Patentschrift 147 819).Since the resinate according to the invention decomposes to a small extent during processing and storage, even in the form of a pharmaceutical preparation, and unpleasant-smelling aliphatic amines still occur in large dilution, it is advantageously mixed with odor-binding substances. Activated carbon or cation exchangers based on styrene-divinyl with sulfonic acid or carboxyl groups are particularly useful (see GDR patent specification 147 819).

Als rektal anwendbare pharmazeutische Präparate kommen z. B. Suppositorien in Betracht, welche aus einer Kombination des Wirkstoffs mit einer Suppositoriengrundmasse bestehen. Als Suppositoriengrundmasse eignen sich z. B. natürliche oder synthetische Triglyceride, Paraffinkohlenwasserstoffe, Polyäthylenglycole oder höhere Alkanole. Ferner können auch Gelatine-Rektalkapseln verwendet werden, die eine Kombination des Wirkstoffkomplexes mit einer Grundmasse enthalten; als Grundmassenstoffe kommen z. B. flüssige Triglyceride, Polyäthylenglykole oder Paraffinkohlenwasserstoff in Frage.As rectally applicable pharmaceutical preparations come, for. B. suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository base z. B. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which contain a combination of the active ingredient complex with a base material; come as base materials z. B. liquid triglycerides, polyethylene glycols or paraffin hydrocarbon in question.

Die vorliegende Erfindung betrifft ebenfalls die Verwendung des Resinats der Formel I, vorzugsweise zur Behandlung von Entzündungen, in erster Linie von entzündlichen chronischen Erkrankungen des rheumatischen Formenkreises, besonders der chronischen Arthritis.The present invention also relates to the use of the resinate of the formula I, preferably for the treatment of inflammation, primarily inflammatory chronic diseases of the rheumatic type, in particular chronic arthritis.

Die nachfolgenden Beispiele illustrieren die oben beschriebene Erfindung. Temperaturen sind in Celsiusgraden, Drucke in mbar angegeben.The following examples illustrate the invention described above. Temperatures are given in degrees Celsius, pressures in mbar.

Beispiel 1:Example 1:

Konditionierung des Harzes: 100 g Cholestyramin (Duolite0 143) mit einer Korngrösse von 40 oder 80 um werden in 500 ml 2N Natriumhydroxid suspendiert. Die Mischung wird während 4 Stunden bei 50° gerührt. Die überstehende Lösung wird abdekantiert und das Harz 4 mal mit deionisiertem Wasser gewaschen. Dann werden 500 ml 2N Salzsäure zugegeben und die Mischung wieder während 4 Stunden bei 50° gerührt. Die überstehende Flüssigkeit wird wieder abdekantiert und das Harz mit einem Überschuss von heissem deionisiertem Wasser gewaschen bis der pH der abdekantierten Lösung zwischen 8 und 9 liegt. Danach wird das Harz während 2 Stunden in Isopropylalkohol suspendiert um mögliche organische Verunreinigungen zu entfernen. Danach wird das Harz filtriert und 2 mal mit deionisiertem Wasser gewaschen. Die Trocknung zur Gewichtskonstanz erfolgt bei 50° im Vakuum.

  • a) Beladung des Harzes mit Wirkstoff: 100 g Diclofenac-natrium werden in 5 Liter deionisiertem Wasser aufgelöst und dann 100 g konditioniertes Cholestyramin (80 µm) langsam in dieser Lösung verteilt. Die Mischung wird während ca. 12 Stunden bei 50° gerührt. Das erhaltene Wirkstoffresinat wird abfiltriert und bis zur Gewichtskonstanz bei 50° im Vakuum getrocknet.
  • b) Beladung des Harzes mit Wirkstoff: 100 g Diclofenac-natrium werden in 5 Liter deionisiertem Wasser aufgelöst und dann 200 g konditioniertes Cholestyremin (40 µm) langsam in dieser Lösung verteilt. Die Mischung wird während ca. 12 Stunden bei 50° gerührt. Das erhaltene Wirkstoffresinat wird abfiltriert und bis zur Gewichtskonstanz bei 50° im Vakuum getrocknet.
Conditioning of the resin: 100 g cholestyramine (Duolite 0 143) with a grain size of 40 or 80 µm are suspended in 500 ml 2N sodium hydroxide. The mixture is stirred at 50 ° for 4 hours. The supernatant solution is decanted off and the resin is washed 4 times with deionized water. Then 500 ml of 2N hydrochloric acid are added and the mixture is again stirred at 50 ° for 4 hours. The supernatant liquid is decanted off again and the resin is washed with an excess of hot deionized water until the pH of the decanted solution is between 8 and 9. The resin is then suspended in isopropyl alcohol for 2 hours to remove any organic contaminants. The resin is then filtered and washed twice with deionized water. Drying to constant weight takes place at 50 ° in a vacuum.
  • a) Loading of the resin with active ingredient: 100 g of diclofenac sodium are dissolved in 5 liters of deionized water and then 100 g of conditioned cholestyramine (80 μm) are slowly distributed in this solution. The mixture is stirred at 50 ° for about 12 hours. The active resin resinate obtained is filtered off and dried to constant weight at 50 ° in vacuo.
  • b) Loading of the resin with active ingredient: 100 g of diclofenac sodium are dissolved in 5 liters of deionized water and then 200 g of conditioned cholestyremine (40 μm) are slowly distributed in this solution. The mixture is stirred at 50 ° for about 12 hours. The active resin resinate obtained is filtered off and dried to constant weight at 50 ° in vacuo.

Beispiel 2:Example 2:

Tabletten enthaltend Wirkstoff entsprechend 150 mg Diclofenac-Na können folgendermassen hergestellt werden:

Figure imgb0005
Tablets containing an active ingredient corresponding to 150 mg of diclofenac-Na can be produced as follows:
Figure imgb0005

Herstellung: Sämtliche festen Ingredienzien werden zunächst durch ein Sieb von 0,6 mm Maschenweite getrieben. Dann werden das Wirkstoffresinat, die Lactose, das Talkum, das Magnesiumstearat und die Hälfte der Stärke vermischt. Die andere Hälfte der Stärke wird in 40 ml Wasser suspendiert und diese Suspension zu einer siedenden Lösung des Polyäthylenglykols in 100 ml Wasser hinzugegeben und mit der entstandenen Suspension das obige Gemisch, wenn nötig unter Hinzufügen von Wasser, granuliert. Das Granulat wird über Nacht bei 35° getrocknet, durch ein Sieb mit 1,2 mm Maschenweite getrieben und zu beidseitig gewölbte Tabletten von etwa 8 mm Durchmesser verpresst.Production: All solid ingredients are first passed through a sieve with a mesh size of 0.6 mm. Then the drug resinate, lactose, talc, magnesium stearate and half the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the above mixture is granulated with the resulting suspension, if necessary with the addition of water. The granules are dried overnight at 35 °, passed through a sieve with a mesh size of 1.2 mm and compressed to tablets which are curved on both sides and have a diameter of approximately 8 mm.

Beispiel 3:Example 3:

Tabletten enthaltend Wirkstoff entsprechend 150 mg Diclofenac-Na können folgendermassen hergestellt werden:

Figure imgb0006
Tablets containing an active ingredient corresponding to 150 mg of diclofenac-Na can be produced as follows:
Figure imgb0006

Herstellung: Sämtliche festen Ingredienzien werden zunächst durch ein Sieb von 0,6 mm Maschenweite getrieben. Dann wird das Wirkstoff-Resinat mit allen Hilfsstoffen vermischt. Die fertige Tabletten-Grundmasse wird alsdann zu Tabletten von 9 mm Durchmesser und 230 mg Gewicht verpresst.Production: All solid ingredients are first passed through a sieve with a mesh size of 0.6 mm. Then the active substance resinate is mixed with all auxiliary substances. The finished tablet base is then compressed into tablets of 9 mm in diameter and 230 mg in weight.

Beispiel 4:Example 4:

2000 g Wirkstoff-Resinat gemäss Beispiel 1a werden in 10 000 Kapseln (Grösse 1) abgefüllt. Jede Kapsel enthält 100 mg Wirkstoff.2000 g of resinate according to Example 1a are filled into 10,000 capsules (size 1). Each capsule contains 100 mg of active ingredient.

Beispiel 5:Example 5:

3 000 g Wirkstoff-Resinat gemäss Beispiel 1a werden mit 10 g Aktivkohle gründlich vermischt und durch ein Sieb von 0,6 mm Maschenweite getrieben. Danach wird die Mischung in 10 000 Kapseln (Grösse 1) abgefüllt. Jede Kapsel enthält 150 mg Wirkstoff.3,000 g of resinate according to Example 1a are thoroughly mixed with 10 g of activated carbon and passed through a sieve with a mesh size of 0.6 mm. The mixture is then filled into 10,000 capsules (size 1). Each capsule contains 150 mg of active ingredient.

Beispiel 6:Example 6:

20 g Traganth, 6 g p-Hydroxbenzoesäuremethylester und 1,5 g p-Hydroxybenzeosäurepropylester werden in 2 Liter Wasser bei 80 - 90°C aufgelöst. Das Erhaltene Gel wird abgekühlt und 75 g des oben erhaltenen, trockenen Wirkstoff-Resinat gemäss Beispiel 1b) und 5 g Zerolit 225 (Teilchengrösse 50 µ) werden zugefügt und unter Verwendung eines Homogenisators gründlich dispergiert. 2 000 g Sorbit-Lösung 70 % werden zugesetzt. Dann wird der Dispersion Wasser bis zum Endvolumen von 5 Liter zugefügt, so dass die erhaltene Suspension etwa 1,5 % Resinat enthält. Ein Teelöffel dieser Suspension enthält ungefähr eine Dosis, die 50 mg Diclofenacnatrium entspricht. Genau ist diese Dosis in 5 ml Suspension enthalten.20 g of tragacanth, 6 g of methyl p-hydroxybenzoate and 1.5 g of propyl p-hydroxybenzoate are dissolved in 2 liters of water at 80-90 ° C. The gel obtained is cooled and 75 g of the above-obtained dry resin resinate according to Example 1b) and 5 g of Zerolit 225 (particle size 50 μ) are added and thoroughly dispersed using a homogenizer. 2,000 g sorbitol solution will be 70% added. Water is then added to the dispersion to the final volume of 5 liters, so that the suspension obtained contains about 1.5% resinate. A teaspoon of this suspension contains approximately a dose equivalent to 50 mg of diclofenac sodium. Exactly this dose is contained in 5 ml suspension.

Beispiel 7:Example 7:

3 g des gemäss Beispiel 1a erhaltenen Diclofenac-Resinat werden in einem geschmolzenen Gemisch von 20 g Polyäthylenglykol 4000 und Polyäthylenglykol 1000 (1 : 1) suspendiert. Die erhaltene Schmelzmasse wird in Suppositorienformen gegossen und dann abgekühlt. Jedes Rektal-Suppositorium wiegt ca. 2 g und enthält Wirkstoff entsprechend 150 mg Diclofenac-Na.3 g of the diclofenac resinate obtained according to Example 1a are suspended in a molten mixture of 20 g of polyethylene glycol 4000 and polyethylene glycol 1000 (1: 1). The melt mass obtained is poured into suppository molds and then cooled. Each rectal suppository weighs approx. 2 g and contains the active ingredient corresponding to 150 mg of diclofenac-Na.

Beispiel 8:Example 8:

60 g Duolite® A 161 (durchschnittliche Teilchengrösse: 80 µm) werden in einem Liter 1,5 N Natriumhydroxid suspendiert, und die Suspension wird auf einem Wasserbad auf 50° erhitzt. Nach 4 bis 5 Stunden wird die Suspension filtriert und das Filtrat mit deionisiertem Wässer gewaschen. Das so erhaltene Harz wird in einem Liter 2N Salzsäure suspendiert und bei 50° während 4 bis 5 Stunden gerührt. Das Harz wird abfiltriert und das Filtrat mit deionisiertem Wasser gewaschen. Die oben erwähnte Schritte werden zweimal wiederholt.60 g of Duolite® A 161 (average particle size: 80 µm) are suspended in one liter of 1.5 N sodium hydroxide, and the suspension is heated to 50 ° on a water bath. After 4 to 5 hours the suspension is filtered and the filtrate washed with deionized water. The resin thus obtained is suspended in one liter of 2N hydrochloric acid and stirred at 50 ° for 4 to 5 hours. The resin is filtered off and the filtrate is washed with deionized water. The above steps are repeated twice.

Das erhaltene Harz wird in Isopropylalkohol suspendiert und während 4 bis 5 Stunden gerührt. Das abfiltrierte Harz wird bei 50° im Vakuum getrocknet.The resin obtained is suspended in isopropyl alcohol and stirred for 4 to 5 hours. The resin filtered off is dried at 50 ° in vacuo.

15 g Diclofenac-Natrium werden in einem Liter deionisiertem Wasser gelöst. 15 g des erhaltenen aktivierten Harzes werden in der hergestellten Lösung suspendiert und die Suspension während 12 Stunden gerührt. Danach wird das erhaltene Resinat abfiltriert und bei 50° unter Vakuum getrocknet.15 g of diclofenac sodium are dissolved in one liter of deionized water. 15 g of the activated resin obtained are suspended in the solution prepared and the suspension is stirred for 12 hours. The resinate obtained is then filtered off and dried at 50 ° under vacuum.

Aus diesem Resinat können Tabletten, Kapseln, Suspensionen und Suppositorien gemäss den Angaben in den Beispielen 2 bis 6 hergestellt werden.Tablets, capsules, suspensions and suppositories can be produced from this resinate as described in Examples 2 to 6.

Claims (12)

1. A resinate of the formula
Figure imgb0013
wherein Am¢ is a strongly basic copolymer of styrene and divinylbenzene which is in cationic form, said copolymer containing the sum of m + n quaternary ammonium groups and also containing, as main structural unit, the grouping of the formula
Figure imgb0014
Xe is an anion of an acid different from the anion of the formula
Figure imgb0015
and m and n denote the entire ionic capacity of the copolymer, and the molecular weight of which is about 107 to about 109.
2. A resinate according to claim 1, wherein the stoichiometric ratio of active ingredient to ion exchange resin is about 1 :1 to 1 : 2.
3. A resinate according to claims 1 and 2, wherein the particle size of the resin is between 20 and 200 µm.
4. A resinate according to claim 3, wherein the particle size of the resin is between 40 and 100 µm.
5. A resinate according to claims 1 - 4, wherein the crosslinkage of the resin is between 2 and 8 %.
6. A resinate according to claim 5, wherein the crosslinkage of the resin is between 2 and 4 %.
7. A resinate according to claims 1 - 6, wherein cholestyramine is used as the anion exchange polymer.
8. A resinate according to claims 1 - 7, wherein cholestyramine having a degree of polymerisation of approximately 108 is used as the copolymer of styrene and divinylbenzene.
9. A resinate of the formula I according to claim 1 for use in the treatment of the human or animal body.
10. A pharmaceutical composition which contains a resinate of the formula I according to claim 1.
11. Use of a resinate of the formula I according to claim 1 for the preparation of pharmaceutical compositions.
12. A process for the preparation of a resinate according to claims 1-8, which comprises reacting o-(2,6-dichloroanilino)phenylacetic acid, or a salt thereof, with a resin of the formula
[Am⊕] [OHe]m+n

or a salt thereof with an acid.
EP84810008A 1983-01-12 1984-01-06 Substituted carboxylic-acid resins, process for their manafacture, use thereof and pharmaceutical compositions containing these resins Expired EP0122219B1 (en)

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CS17884A2 (en) 1989-10-13
FI840069A0 (en) 1984-01-09
IE56545B1 (en) 1991-08-28
NL8400098A (en) 1984-08-01
AU2323084A (en) 1984-07-19
RO88481A (en) 1986-01-30
AT391467B (en) 1990-10-10
HUT34151A (en) 1985-02-28
DZ593A1 (en) 2004-09-13
DE3400491C2 (en) 1988-11-10
SE457959B (en) 1989-02-13
US4510128A (en) 1985-04-09
FI82682B (en) 1990-12-31
DK166683B1 (en) 1993-06-28
PL142737B1 (en) 1987-11-30
CA1218077A (en) 1987-02-17
MA20000A1 (en) 1984-10-01
NO162862B (en) 1989-11-20
MTP943B (en) 1984-06-05
LU85171A1 (en) 1984-10-24
SE8400098D0 (en) 1984-01-10
PT77932A (en) 1984-02-01
MC1564A1 (en) 1984-11-12
KR900006747B1 (en) 1990-09-20
GB2134529A (en) 1984-08-15
GR79793B (en) 1984-10-31
CH655507B (en) 1986-04-30
AU570230B2 (en) 1988-03-10
AR240310A1 (en) 1990-03-30
IT1177501B (en) 1987-08-26
NZ206815A (en) 1986-08-08
ATE37378T1 (en) 1988-10-15
GB2134529B (en) 1986-09-24
ES528770A0 (en) 1985-05-01
SE8400098L (en) 1984-07-13
DE3474152D1 (en) 1988-10-27
DD218373A5 (en) 1985-02-06
KR840007562A (en) 1984-12-08
PH21795A (en) 1988-02-29
PT77932B (en) 1986-07-22
NO840090L (en) 1984-07-13
JPH0257058B2 (en) 1990-12-03
NO162862C (en) 1990-02-28
DK11884D0 (en) 1984-01-11
ZA84212B (en) 1984-08-29
IT8447527A0 (en) 1984-01-10
HU190750B (en) 1986-10-28
HK90390A (en) 1990-11-09
JPS59134759A (en) 1984-08-02
ZW484A1 (en) 1984-08-08
CS269954B2 (en) 1990-05-14
FR2542735B1 (en) 1986-04-18
BE898649A (en) 1984-07-11
FI82682C (en) 1991-04-10
IE840049L (en) 1984-07-12
FI840069A (en) 1984-07-13
FR2542735A1 (en) 1984-09-21
IL70660A (en) 1987-08-31
DK11884A (en) 1984-07-13
DE3400491A1 (en) 1984-07-12
OA07628A (en) 1985-05-23
IL70660A0 (en) 1984-04-30
GB8400251D0 (en) 1984-02-08
EP0122219A3 (en) 1985-05-08
EG16562A (en) 1991-12-30
ATA784A (en) 1990-04-15
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